In spite of the many alterations in cell physiology that generally accompany the malignant state, many tumors retain some normal regulatory mechanisms. Thus 60 to 70% of all human breast tumors contain the estradiol receptor. When the receptor is present, there is a 55% chance that the patient will respond to hormonal therapy. If the receptor is absent, there is less than 10% chance of response to hormone therapy. Available hormonal manipulations include ablative procedures such as the removal of ovaries, adrenal glands, or pituitary, and additive procedures such as the administration of estrogen, or progestins. Some tumors, therefore, appear to recognize and, indeed, require the same signals that act during the normal estrus cycle to induce the controlled hypertrophy and hyperplasia of the healthy uterus. We feel that study of these tumors, with their vestige of normal growth control will provide an important handle to dissect the nature of hormone-responsive and non-responsive tumor growth. Our first objective is to examine the nature and specificity of interaction of the estradiol-receptor complex with chromatin and the components of chromatin, which may be the nuclear hormone acceptor. Secondly, we wish to apply this information to an analysis of human and other mammalian endocrine tumors that do or do not respond to endocrine therapy. These studies will test our specific hypothesis that the repeated DNA sequences conspicuously present only in eukaryotic chromosomes have a role in the recognition and binding of the estradiol-receptor complex; and that this recognition and binding system may be altered in some mammary cancers.